The dopamine hypothesis of schizophrenia proposed that positive symptoms of the illness are associated with hyperactivity of dopamine transmission. This hypothesis was recently supported by the observation in three studies that the amphetamine-induced reduction in [123[] IBZM and [11C]raclopride binding potential (BP) was elevated in patients with schizophrenia. The larger displacement of the antagonists [123I]IBZM or [11C]raclopride following amphetamine challenge in patients with schizophrenia might result from a larger increase in dopamine synaptic concentration following amphetamine (i.e. presynaptic factors) or from an increased affinity of D2 receptors for dopamine (i.e. postsynaptic factors), or from some combination of both factors. Available data and current methods do not allow to tease apart the respective contributions of these factors, because of the lack of in vivo methods to measure affinity of 132 receptors for agonists. In spite of the fact that D2 antagonist benzamide radioligands such as [123I]BZM and [11C]raclopride have contributed tremendously to our understanding of endogenous synaptic dopamine concentrations, they have been plagued by their relatively low sensitivity and ceiling effect (following psychostimulant challenges) which are presumably related to the fact that antagonist D2 radioligands bind to both high and low affinity states. The endogenous agonist dopamine is expected to compete efficiently with a D2 agonist ligand such as [11C]NPA than binds preferentially to the high affinity configuration unlike antagonist ligand such as []23I]IBZM or [1lC]raclopride that fail to distinguish between affinity states. We present preliminary evidence supporting the hypothesis that the D2 agonist radioligands [11C]NPA will provide a superior tool to study changes in intrasynaptic dopamine in the living brain. This application proposes to characterize the in vivo binding of [1tC]NPA in baboons (contribution of high and low agonist affinity sites to in vivo binding), to determine the whole body dosimetry, file an IND and to characterize this radiotracer in healthy human subjects (test/retest reliability and vulnerability to endogenous dopamine) which would lead to the eventual application of this radiotracer to study the high affinity D2 receptor sites in schizophrenia. The overall goal of this study is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with schizophrenia.